Insights into the N-Heterocyclic Carbene (NHC)-Catalyzed Oxidative Î³

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2018, 83, 8543−8555

Insights into the N‑Heterocyclic Carbene (NHC)-Catalyzed Oxidative γ‑C(sp3)−H Deprotonation of Alkylenals and Cascade [4 + 2] Cycloaddition with Alkenylisoxazoles Xue Li,† Yanyan Wang,† Yang Wang,‡ Mingsheng Tang,† Ling-Bo Qu,† Zhongjun Li,*,† and Donghui Wei*,†

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†

The College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Avenue, Zhengzhou, Henan 450001, People’s Republic of China ‡ Department of Material and Chemical Engineering, Zhengzhou University of Light Industry, 136 Science Avenue, Zhengzhou, Henan 450002, People’s Republic of China S Supporting Information *

ABSTRACT: The N-heterocyclic carbene (NHC)-catalyzed oxidative C− H deprotonations have attracted increasing attention; however, the general mechanism regarding this kind of oxidative organocatalysis remains unclear. In this paper, the competing mechanisms and origin of the stereoselectivity of the NHC-catalyzed oxidative γ-C(sp3)−H deprotonation of alkylenals and cascade [4 + 2] cycloaddition with alkenylisoxazoles were systematically investigated for the first time using density functional theory (DFT). The computed results indicate that the oxidation of the Breslow intermediate by 3,3′,5,5′-tetra-tert-butyl diphenoquinone (DQ) via a hydride transfer to oxygen (HTO) pathway is the most favorable among the four competing pathways. In addition, the analyses demonstrate that oxidant DQ plays a double role, i.e., strengthening the acidity of the hydrogen of the γ-carbon of alkylenal and forming π···π interactions with conjugated CC bonds to promote the γ-C(sp3)−H deprotonation. The NHC catalyst acts as a Lewis base, and the hydrogen-bond network between the NHC and the substrate formed in the key Michael addition step is responsible for the origin of the stereoselectivity. Further DFT calculations reveal that the nonpolar solvent can stabilize the nonpolar R isomer but destabilize the polar S isomer for the stereoselectivitydetermining transition states, thus improving the stereoselectivity. esterification and amidation of aldehydes (Scheme 1A),8,11 the NHC-catalyzed oxidative α-C(sp3)−H deprotonation of aliphatic aldehydes and cascade [2 + n] (n = 2, 3, 4) cycloadditions (Scheme 1B),3a,b,12 the NHC-catalyzed oxidative β-C(sp 3)−H deprotonation of saturated carbonyl compounds and cascade [3 + n] (n = 2, 3) cycloadditions (Scheme 1C),3c,13 and the NHC-catalyzed oxidative γC(sp3)−H deprotonation of enals and cascade [4 + n] (n = 2, 3) cycloadditions (Scheme 1D).14 As shown in Scheme 1, almost all of the NHC-catalyzed oxidative reactions contain the oxidative transformation from the Breslow intermediate to the acylazolium intermediate. However, the general mechanism regarding the oxidation of the Breslow intermediate involved in NHC catalysis is obscure. Guided by the previous report,15 four distinctive pathways might be possible for the oxidation of the Breslow intermediate. Two of the possible pathways are a one-step hydride transfer to the O or C atoms of DQ (denoted as the HTO/HTC pathways, respectively).16 In addition, Chi’s group proposed a single electron transfer (SET) followed by a subsequent hydrogen-atom transfer (HAT) (denoted as the

1. INTRODUCTION N-Heterocyclic carbenes (NHCs) have emerged as powerful and elegant organocatalysts in a variety of newly developed and unprecedented enantioselective transformations.1 Great progress has been made in NHC-catalyzed inert C−H deprotonation/functionalization over the past few years.2 In particular, the NHC-catalyzed oxidative C(sp3)−H deprotonations of saturated and unsaturated carbonyl compounds have been and continue to be one of the hottest topics in the area of asymmetric synthesis.3 Inspired by enzyme-catalyzed approaches,4 various organic compounds, including the aromatic nitro/nitroso derivatives,5 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO),6 methyltetra-O-acetylriboflavin (MeFl),7 and 3,3′,5,5′-tetra-tert-butyl diphenoquinone (DQ),8 have been shown to act as oxidants in the oxidative carbene catalysis.9 Notably, the organic oxidant DQ has demonstrated the oxidation of the Breslow intermediate involved in NHC organocatalysis.8 Since then the application of the oxidant DQ was quickly developed and expanded to the NHC-catalyzed oxidative annulation reactions (Scheme 1).10 To date, the carbonyl carbon and α-, β-, and γcarbon atoms of the saturated/unsaturated aldehydes have been successfully activated by the NHC catalyst in the presence of the DQ oxidant, i.e., the NHC-catalyzed oxidative © 2018 American Chemical Society

Received: May 1, 2018 Published: June 21, 2018 8543

DOI: 10.1021/acs.joc.8b01112 J. Org. Chem. 2018, 83, 8543−8555

Article

The Journal of Organic Chemistry Scheme 1. Representative NHC-Catalyzed Oxidative Functionalizations of the Carbonyl Compounds

Scheme 2. NHC-Catalyzed Oxidative [4 + 2] Annulation of Enal and Alkenylisoxazole

C(sp3)−H bond of the carbonyl compounds be deprotonated in this type of oxidative reaction? (4) What are the roles of the oxidant DQ and catalyst NHC? (5) What is the origin of the stereoselectivity? These questions and our interest in NHC catalysis21 prompt us to perform this theoretical study regarding the possible mechanism and stereoselectivity of the organocatalytic oxidative reactions. In the present study, we selected the NHC-catalyzed oxidative [4 + 2] annulation14d of enal R1 and alkenylisoxazole R2 depicted in Scheme 2 as the reaction model, which was used to produce cyclohexenone P with high stereoselectivity. In the following sections, we employed a density functional theory (DFT) method to investigate the general mechanism, disclose the roles of the oxidant DQ and catalyst NHC, elucidate the origin of the stereoselectivities, and explore the

SET−HAT pathway) for the oxidative process (as depicted in Scheme 1D),13a,17 and the fourth possible pathway is the HAT followed by the SET (denoted as HAT−SET pathway).18 Although there are several mechanistic studies regarding the NHC-catalyzed β-/γ-C(sp3)−H deprotonation/functionalization of saturated/unsaturated esters without the presence of an oxidant,19 to the best of our knowledge, the general mechanism of the NHC-catalyzed oxidative C(sp3)−H deprotonation/ functionalization of aldehydes/enals remains unclear. Despite tremendous efforts that have been contributed in experiments,14,20 there are still several key questions that need to be answered in this kind of reaction, as follows: (1) How can the oxidative transformation from the Breslow intermediate to the acylazolium intermediate proceed in this type of reaction? (2) Which is the most favorable oxidative pathway among the above four pathways? (3) How can the saturated γ8544


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The Journal of Organic Chemistry Scheme 3. Possible Catalytic Cycle of the Reaction

Figure 1. Relative Gibbs free energy profiles of steps 1−5. reported by Houk,27 Tantillo,28 Sunoj,29 and so on.24b,30 The calculations were performed at the M06-2X31 level of DFT using the appropriate integral equation formalism polarizable continuum model (IEF-PCM)32 in a toluene or THF solvent. DFT methods, including M06-2X(-D3), ωB97X-D, B3LYP, and B3LYP-D3BJ, incorporating seven computational levels (denoted as L1−7) were used to justify the energy viability of the stereochemical transition states involved in the stereoselectivity-determining step. The noncovalent interaction (NCI) analysis was conducted to clarify the

substituent and solvent effects for this kind of NHC-catalyzed oxidative reaction.

2. COMPUTATIONAL DETAILS All calculations were performed by Gaussian 0922 using density functional theory, which has been widely used to clarify the detailed mechanisms of the enzyme-catalyzed,23 organocatalytic,24 and transition metal-catalyzed25 reactions and other theoretical studies.26 The more successful applications can be found in the references 8545


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The Journal of Organic Chemistry Scheme 4. Possible Pathways for the Oxidation Step (kcal/mol)

controlling factors of the stereoselectivity-determining step, which was plotted by NCIplot (version 1.0)33 and Multiwfn (version 3.3.8).34 The optimized geometrical structures were rendered by CYLView software.35 The influence of different temperatures on the calculated results was also tested for the first step, and more details can be found in the Supporting Information. The activation free energy of the SET process was computed from Marcus theory.36 The natural bond orbital (NBO) and distortion/ interaction37 analyses, which can provide highly insightful methods for understanding the roles of the oxidant and catalyst, were performed to shed light on the influencing factors of the oxidation and γ-C(sp3)−H deprotonation processes.

Re-face of R1 can be ignored. The second step is a [1,2]proton transfer assisted by the in-situ-generated base CsHCO3 via the seven-membered ring transition state TS2 (ΔG‡ = 4.2 kcal/mol, Figure 1) to form the Breslow intermediate M2. In addition, the other possible direct/HCO3−/CO32−-assisted proton transfer pathways via the corresponding transition states TS2a/TS2b/TS2c (ΔG‡ = 39.1/11.2/5.6 kcal/mol, Figure S3 of the Supporting Information) were also considered and studied, and their higher energy barriers than that via TS2 (ΔG‡ = 4.2 kcal/mol) imply that the three pathways can be neglected. The third step is the oxidation of the Breslow intermediate via a hydride transfer to oxygen (HTO) pathway. As shown in Figure 1, the hydride H4 transfers from the O2 atom in the Breslow intermediate M2 to the O1′ atom in DQ to provide the intermediate M3 via the transition state TS3. The low energy barrier via TS3 (ΔG‡ = 7.8 kcal/mol) indicates that this process easily occurs at the experimental condition. Notably, the intermediate M3 is composed of the cation intermediate M03 and anion [DQH]−, and the energy difference between M3 and M03+[DQH]− is very high (ΔG = 32.9 kcal/mol, Scheme 4); thus, we believe the following processes should be initiated from M3 rather than M03. As discussed in the Introduction, we considered and investigated the other three possible pathways (i.e., the HTC, SET−HAT, and HAT−SET pathways). As depicted in Scheme 4, in the HTC pathway, the hydride H4 transfers from the O2 atom in M2 to the C3′ atom of DQ to give the intermediate M3HTC via the transition state TS3HTC (ΔG‡ = 28.5 kcal/mol). Therefore, this HTC pathway is unlikely to occur under these experimental conditions and can be safely

3. RESULTS AND DISCUSSION 3.1. Possible Mechanism. As depicted in Scheme 3, we have suggested a possible mechanism for the reaction. The entire catalytic cycle is initiated at the deprotonation of preNHC by base CsCO3− to generate the real catalyst NHC. The whole catalytic cycle contains eight steps: (1) nucleophilic addition of NHC to R1; (2) [1,2]-proton transfer; (3) oxidation process; (4) γ-C(sp3)−H deprotonation; (5) rotation process; (6) Michael addition; (7) ring-closure process; and (8) regeneration of NHC. The related Gibbs free energy profiles of steps 1−5 are presented in Figure 1, and the energies of all of the minima are relative to the energy of NHC+R1 (0.0 kcal/mol) unless otherwise specified. As shown in Figure 1, the first step is the nucleophilic attack on the Re-/Si-face of R1 by the catalyst NHC to afford the intermediate Re/Si-M1 via the transition state Re/Si-TS1. The energy barrier via Re-TS1 (15.5 kcal/mol) is 4.0 kcal/mol higher than that via Si-TS1 (11.5 kcal/mol), so the following processes initiated by the nucleophilic attack of NHC on the 8546


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The Journal of Organic Chemistry

Figure 2. Relative Gibbs free energy profiles of steps 6−8.

The sixth step is a Michael addition, so the energy of NHC +R1+R2 involved in the following processes can be set as 0.0 kcal/mol as the reference, and the related Gibbs free energy profiles of steps 6−8 are shown in Figure 2. As presented in Figures 2 and 3, the intermediate M5 nucleophilically attacks

excluded. Moreover, the possibilities of the hydride transferring to the other three types of carbon (i.e., C2′, C4′, and C5′) were taken into account, and more details can be found in Scheme S1 and Figure S4 of the Supporting Information. As presented in Scheme 4, the SET−HAT pathway contains two processes. In the first process, a single electron transfers from M2 to DQ to accomplish the SET process with the formation of the intermediate radical M3SET and the DQ•− radical. In the second process, the hydrogen atom (H4) transfers (HAT) from the O2 atom of the radical M3SET to the O1′ atom of the DQ•− radical to present the cation intermediate M03 and anion [DQH]−. As revealed by the computed results (Table S5 of the Supporting Information), the activation energy of the SET process is 17.9 kcal/mol, indicating that this process is less energetically favorable than the HTO pathway. Thus, it is not necessary to consider and investigate the following HAT process, and the SET−HAT pathway can be ignored. Further, in the HAT−SET pathway, the hydrogen atom H4 transfers from the O2 atom of M2 to the O1′ atom of DQ to render the radical intermediate M3HAT and the [DQH]• radical, which is followed by a single electron transfer from the radical M3HAT to the [DQH]• radical. The optimized 3-D structures of the intermediates M3HAT and M3SET can be found in the Supporting Information. The relative Gibbs free energy change of the HAT process (ΔG = −7.0 kcal/mol, Scheme 4) implies that this process very easily occurs under such conditions, but the activation energy of the following SET process (ΔG‡ = 19.7 kcal/mol, Scheme 4 and Table S5 of Supporting Information) is much higher than the energy barrier of the HTO pathway (ΔG‡ = 7.8 kcal/mol, Figure 1). Therefore, the HAT−SET pathway can also be ignored. As shown in Scheme 3, the fourth step is a γ-C(sp3)−H deprotonation of the intermediate M3. The Hγ atom of M3 can be abstracted by the in-situ-generated base HCO3− to afford the intermediate M4 via the transition state TS4 (ΔG‡ = 11.3 kcal/mol, Figure 1). The next step is a rotation of dihedral angle C−Cα−Cβ−Cγ in M4 to form the azolium dienolate intermediate M5 via a rotational transition state TS5, which only has a very low energy barrier (3.9 kcal/mol, Figure 1).

Figure 3. Different stereochemical modes involved in the Michael addition step. Numeric value in parentheses refers to the relative Gibbs free energy calculated at the L1 level with respect to the lower energy transition state TS6R.

the Re-/Si-face of R2 via the transition state TS6R/S (Figure 4) to give the intermediate M6R/S, in which the Cγ−C5 bond is formed. It should be mentioned that the chiral center (C5) is generated in M6R/S, and the letter “R/S” of M6R/S represents the chirality of the C5 atom. To ensure the selected transition state conformation with the lowest energy, 12 possible conformations have been computed and compared in the Supporting Information, and we only discuss the lowest energy conformation in the main text. As presented in Figure 2, the lower energy barrier of TS6R (13.8 kcal/mol) with respect to that of TS6S (16.2 kcal/mol) indicates that the nucleophilic addition mode of M5 to the Re-face of R2 via TS6R is more energetically favorable. As shown in Figures 2 and 5, the seventh step is a ringclosure process for the generation of the intermediates M7RR/ RS/SR/SS via the corresponding transition states TS7RR/RS/ SR/SS (Figure 5), in which the other chiral center (C6) is formed. Notably, the two letters “RR/RS/SR/SS” after the names of the intermediate M7 and transition state TS7 represent the corresponding chiralities of the C5 and C6 atoms. As presented in Figure 2, the energy barriers via 8547


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Figure 4. Optimized geometries of the key transition states for the catalytic cycle. Hydrogen atoms that are not involved in the reaction have been omitted. Distances are in Angstroms.

Gibbs free energies of TS7RR/RS/SR/SS are 10.9, 15.0, 16.0, and 12.7 kcal/mol, respectively, suggesting that the pathway associated with the transition states TS6R and TS7RR is the most energetically favorable path, which is well consistent with the main product PRR observed in experiment.14d The last step is the dissociation of M7RR/RS/SR/SS for the regeneration of the catalyst NHC and the formation of the products PRR/RS/SR/SS via the relevant transition states TS8RR/RS/SR/SS (Figure 2), and the corresponding energy barriers are equal to 1.0, 6.4, 4.8, and 4.4 kcal/mol, respectively. The energies of products PRR/SS and PRS/SR are 25.2 and 23.0 kcal/mol below that of reactants, respectively, implying the overall reaction is exothermic. 3.2. Predicting of the Different Active Sites in the Intermediates. To understand the reactivity of the α-, β-, and γ-carbon atoms of the key intermediates involved in the reaction, the local reactivity indexes (electrophilic (Pk+) and nucleophilic (Pk‑) Parr functions)38 of the three carbons (i.e., Cα, Cβ, and Cγ) in the Breslow intermediate M2, acylazolium intermediate M3, and azolium dienolate M5 were calculated and are summarized in Table 1. Obviously, the Pk‑ values of the Cα and Cγ atoms in M5 are higher than those in M2 and M3, and the Cγ atom has the highest Pk‑ value (0.448) among the three carbons in M5, indicating that the Cγ atom of M5 would be the most nucleophilic site among the three carbons (i.e., Cα, Cβ, and Cγ). This prediction can satisfactorily explain the chemoselectivity in the reported experiment14d and can be

Figure 5. Different ring-closure modes involved in step 7. Numeric values in parentheses refer to the relative Gibbs free energies calculated at the L1 level related to the lowest energy transition state TS7RR.

TS7RR/RS/SR/SS are 2.4, 6.5, 4.8, and 1.5 kcal/mol, respectively. Compared to the lowest Gibbs free energy intermediate M5 in the energy profile (Figure 2), the relative

Table 1. Electrophilic and Nucleophilic Parr Functions (Pk+ and Pk−) for the Atoms (Cα, Cβ, and Cγ) of the Intermediates M2, M3, and M5 M2

M3

M5

Parr function

Cα

Cβ

Cγ

Cα

Cβ

Cγ

Cα

Cβ

Cγ

Pk+ Pk‑

0.002 −0.121

0.0 0.289

0.0 0.004

−0.102 0.010

0.219 −0.011

0.001 0.005

0.001 0.395

0.0 −0.148

0.001 0.448

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nation process. Moreover, the dissociation energies of the bond Cγ−Hγ in M2, R1, and M3 are also reduced significantly (Scheme S2 of the Supporting Information), which are consistent with the above conclusions. To explain why the presence of the oxidant DQ can lower the energy barrier of the γ-C(sp3)−H deprotonation, the distortion/interaction analyses of TS4, TS4b, and TS4c were performed and compared in Table 3, which indicates that a stronger interaction would be responsible for the low energy barrier of TS4. To further explore the type of weak interactions involved in TS4, we performed an NCI analysis. As shown in Figure 8, the π···π interactions between the biphenyl of [DQH]− and the conjugated CC bonds of the substrate should be the key for the stability of TS4 and thus lower the energy barrier of the γ-C(sp3)−H deprotonation. 3.4. Origin of Stereoselectivity. As revealed by the energy profiles in Figure 2, the chiralities of the stereocenters assigned on the C5 and C6 atoms emerge in the Michael addition and ring-closure processes associated with the transition states TS6 and TS7, respectively. However, the energy barriers via the transition states TS6(R/S) are higher than those via the transition states TS7(RR/RS/SR/SS); therefore, the Michael addition is the rate- and stereoselectivity-determining step. Moreover, the relative Gibbs free energy barrier ΔΔG‡ = ΔG‡TS6S − ΔG‡TS6R = 2.4 kcal/ mol, which corresponds to an enantiomeric excess (ee) value of 96% based on the analysis of the Boltzmann distribution equation. This computed value of enantiomeric excess is close to the experimentally observed 82% ee.14d After identifying the stereoselectivity-determining step, we aim to disclose the stereocontrolling factors based on the NCI analysis. As shown in Figure 9, in TS6R, there exists five hydrogen bonds including C−H···O (2.28 Å), C−H···O (2.40 Å), C−H···O (2.44 Å), C−H···O (2.46 Å), and C−H···N (2.47 Å) and one π···π interaction (3.18 Å) between the conjugated CCα−CβCγ bonds and the C5C6 bond. In TS6S, three hydrogen bonds exist including C−H···O (2.17 Å), C−H···O (2.29 Å), and C−H···O (2.53 Å) and three π···π interactions (3.47, 3.84, and 3.92 Å) between NHC and substrate. Comparing the interactions in the stereochemical transition states, TS6R has more hydrogen-bond interactions (namely, a stronger hydrogen-bond network) than TS6S, suggesting that the hydrogen-bond network between NHC and substrate would be the key for determining the stereoselectivity of the reaction. 3.4.1. Substituent Effects. To explore the substituent effects of the NHC-catalyzed oxidative reaction, the reactions of the different enals with alkenylisoxazoles (entries 1−5, as shown in Table 4) were systematically studied in theory. As summarized in Table 4, the relative Gibbs free energy barriers, ΔΔG‡(n) = ΔG‡TS6S(n) − ΔG‡TS6R(n) (n = 1−5), of the stereoselectivitydetermining step is in the following sequence: ΔΔG‡(2) (= 1.3 kcal/mol) < ΔΔG‡(1) (= 2.4 kcal/mol) < ΔΔG‡(3) (= 2.7 kcal/mol) < ΔΔG‡(4) (= 3.2 kcal/mol) < ΔΔG‡(5) (= 3.6 kcal/mol), which is in agreement with the order of the ee values observed in the experiments.14d These data analyses indicate that our computational results are reasonable and reliable. 3.4.2. Solvent Effects. To explore the effects of different solvents on the stereoselectivity of the reaction, we additionally calculated the relative Gibbs free energy barriers of the stereoselectivity-determining step for the reactions in different solvents as depicted in Scheme 5. As summarized in Table 5,

applied to the rational design of similar reactions involving the same intermediates in the future. 3.3. Role of the Oxidant DQ. To understand the role of DQ and the charge transfer process in the third step, NBO analysis was performed to disclose the charge evolution of the acylazolium intermediate M03 and the anion [DQH]− fragments during the oxidation process. As depicted in Figure 6, the NBO charge analysis indicates that there are two

Figure 6. NBO charge evolution during the oxidation process (M03 and [DQH]− refer to the corresponding fragments of TS3 and M3).

electrons transferred from M03 to [DQH]− during the oxidation process, suggesting that DQ is employed as an oxidant to accept 2e− and a proton in this process. To deeply understand the role of the oxidant DQ for the deprotonation process, the NBO analysis of the key atoms (i.e., Cγ and Hγ) was performed on the reactant R1 and the intermediates Si-M1, M2, M3, and M03. As summarized in Table 2, the NBO charge value of the Hγ atom is significantly Table 2. Values of the NBO Charge on Atoms Cγ and Hγ (e) Cγ Hγ

R1

Si-M1

M2

M3

M03

−0.606 0.225

−0.590 0.212

−0.590 0.207

−0.632 0.270

−0.613 0.238

increased in M3 and M03 compared to that in R1, but the charge value of the Hγ atom (0.270 e) in M3 with the presence of DQ is obviously higher than that (0.238 e) in M03 without DQ, implying that the oxidant DQ can further strengthen the acidity of Hγ and thus facilitates the γ-C(sp3)−H deprotonation process. In addition, the acidity of the γ-C−H bond could also be affected by the conjugation with NHC in the intermediate, and the related discussion can be found in the Supporting Information. Furthermore, we also investigated other possible pathways for the γ-C(sp3)−H deprotonations of different intermediates, including the HCO3−-/DQH−-assisted γ-C(sp3)−H deprotonation of M3 via the transition state TS4b/TS4c and the HCO3−-assisted γ-C(sp3)−H deprotonation of R1/M2 via the transition state TS1b/TS3b. As depicted in Figures 1 and 7, the pathway associated with TS4 (ΔG‡ = 11.3 kcal/mol) is more energetically favorable than those associated with TS4b (ΔG‡ = 17.6 kcal/mol), TS4c (ΔG‡ = 17.7 kcal/mol), TS1b (ΔG‡ = 23.4 kcal/mol), and TS3b (ΔG‡ = 42.7 kcal/mol), indicating the oxidant DQ indeed plays an important role in the γ-C(sp3)−H deproto8549


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Figure 7. (A) Relative Gibbs free energy profiles of the γ-C(sp3)−H deprotonation of reactant R1, Breslow intermediate M2, and intermediate M3. (B) 3D structures of the transition states. (energy unit in kcal/mol; distance unit in Angstroms; superscript “a” represents addition of the energy of catalyst NHC without considering further interaction between the calculated species, which significantly cannot affect the energy profiles.)

Table 3. Distortion/Interaction Analysis for the Possible γ-C−H Deprotonation (all values are in kcal/mol) TS4 TS4b TS4c

ΔE‡dist_M03

ΔE‡dist_[DQH]‑

ΔE‡dist_HCO3‑

ΔE‡dist_total

ΔE‡int

20.9 16.5 13.7

0.6

1.5 1.6

23.0 18.1 16.1

−76.6 −44.4 −44.8

2.4

Table 4. Relative Gibbs Free Energy Barriers ΔΔG‡(n) = ΔG‡TS6S(n) − ΔG‡TS6R(n) (n = 1−5) of the StereoselectivityDetermining Step in Entries 1−5 Calculated at the L1 Computational Level entry

Ar1

Ar2

ΔΔG‡(n) (kcal/mol)

ee value (%) in experiment14d

1 2 3 4 5

C6H5 3-ClC6H4 C6H5 C6H5 C6H5

4-FC6H4 C6H5 4-OMeC6H4 4-C6H5C6H4 C6H5

2.4 1.3 2.7 3.2 3.6

82 76 86 87 90

the order of the relative Gibbs free energy barriers ΔΔG‡solvent is ΔΔG‡toluene (= 4.6 kcal/mol) > ΔΔG‡THF (= 2.8 kcal/mol), which is consistent with the order of the experimental observations.14d These data analyses demonstrate that the

Figure 8. Interaction analysis for the transition state TS4. (Green and red represent the weak interaction and steric effect, respectively; the δ value of the isosurface is set to 0.5.)

Figure 9. Interaction analysis for the diastereoisomeric transition states TS6R and TS6S. (Blue, green, and red represent the strong attraction, weak interaction, and steric effect, respectively; δ value of the isosurface is set to 0.5.) 8550


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The Journal of Organic Chemistry Scheme 5. NHC-Catalyzed Oxidative Reactions in Different Solvents

influences the stereoselectivity of the reaction.14d The solvent polarity can affect the selectivity of the organic reactions, which has also been supported by the other excellent theoretical reports.39 3.5. Role of the Catalyst. To elucidate the role of the catalyst NHC in these new kinds of oxidative reactions, we performed a global reactivity index (GRI) analysis,38c,40 which has been proved to be an efficient tool by many theoretical investigations.21b,41 As summarized in Table 6, the nucleo-

Table 5. Relative Gibbs Free Energy Barriers ΔΔG‡solvent = ΔG‡(TS6Ssolvent) − ΔG‡(TS6Rsolvent) (solvent = toluene or THF) for the Other Reaction Models Calculated at the L1 Computational Levela

Table 6. Energies of HOMO (EH) and LUMO (EL), Electronic Potential (μ), Chemical Hardness (η), Global Electrophilicity (ω), and Global Nucleophilicity (N) of the Reactant R1 and Some Intermediates Si-M1, M2, M3, M4, and M5

solvent

ΔΔG‡solvent (kcal/mol)

ee value (%) in experiment14d

toluene THF

4.6 2.8

75 50

R1 Si-M1 M2 M3 M4 M5

a

The dielectric constants of toluene and THF are equal to 2.4 and 7.4, respectively.

nonpolar solvent is beneficial for the enhancement of the ee values of this oxidative reaction. To further confirm the influence of the solvent polarity on the stereoselectivity-determining step, we calculated and analyzed the electrostatic potential surface (EPS) (Figure 10) of the stereochemical transition states TS6R and TS6S. As shown in Figure 10, TS6Stoluene/TS6STHF (dipole moment μ = 11.4/12.8 D) has a stronger polarity than TS6Rtoluene/ TS6R THF (μ = 5.7/6.3 D) in toluene/THF solvent, respectively. Therefore, the nonpolar toluene can further lower the energy of TS6Rtoluene but increase the energy of TS6Stoluene, which implies that the solvent polarity indeed

EH (au)

EL (au)

μ (au)

η (au)

ω (eV)

N (eV)

−0.290 −0.257 −0.205 −0.183 −0.224 −0.224

−0.082 −0.058 −0.068 −0.094 −0.064 −0.064

−0.186 −0.158 −0.136 −0.139 −0.144 −0.144

0.208 0.199 0.137 0.089 0.159 0.160

2.273 1.702 1.844 2.945 1.786 1.766

2.390 3.290 4.716 5.312 4.199 4.193

philicity of enal R1 is significantly increased after the nucleophilic addition of the catalyst on the carbonyl carbon. Hence, it can be revealed by the GRI analysis that the NHC catalyst herein mainly works as a Lewis base to improve the nucleophilicity of enal R1 and thus facilitates the nucleophilic attack by M5 on the olefin carbon of the reactant R2. 3.5.1. Efficiency of the NHC Catalysts. To explore the general principle on the efficiency of the NHC catalysts, we additionally investigated the rate- and stereoselectivity-

Figure 10. Electrostatic potential surface analysis of the transition states TS6Rtoluene/TS6RTHF and TS6Stoluene/TS6STHF. (Blue and red represent the positive and negative electrostatic potentials, respectively.) 8551


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able pathway results in the RR configurational product, which is in agreement with the experiments. Through further NBO and NCI analyses, we found that the oxidant DQ can promote the γ-C(sp3)−H deprotonation by strengthening the acidity of the γ-C(sp3)−H bond and forming noncovalent interactions with the substrate to stabilize the corresponding transition state. The strength of the hydrogenbond network involved in the stereochemical transition state and the solvent effect should be responsible for the stereoselectivity of the reaction. The catalyst NHC was proved to work as Lewis base to strengthen the nucleophilicity of the substrate in this type of oxidative reaction by the GRI analysis. This theoretical study should be useful for understanding the general mechanism of NHC-catalyzed oxidative reactions and thus provides valuable clues regarding the rational design of these kinds of organocatalytic oxidative reactions with high stereoselectivity.

determining step in the reactions of R1 and R2solvent catalyzed by different NHC catalysts (as shown in Scheme 6). As shown Scheme 6. Other Oxidative Reactions Catalyzed by Different NHC Catalysts in Different Solvents

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Table 7. Global Nucleophilicity (N) of M5NHCs and the Corresponding Energy Barriers ΔG‡(TS6RNHCs) (NHCs = NHC, NHC1, or NHC2) by Utilizing Different Catalysts in Different Solvents catalyst

solvent

N (eV) of M5NHCs

ΔG‡(TS6RNHCs) (kcal/mol)

yield (%) in experiment14d

NHC NHC1 NHC2

toluene toluene DCM

4.193 4.210 4.009

14.4 12.8 17.6

71 72 87

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01112. Computational details, test results of computational methods, optimized geometries of the stationary points, direct/HCO3−/CO32−-assisted proton transfer for the formation of M2, other HTC possible pathways during the oxidation process, different conformers and configurations of TS6, dissociation energies of the Cγ−Hγ bonds in intermediates, possible intermolecular SET processes, oxidation potential calculations, barriers of the outer-sphere single electron transfer, absolute singlepoint energies and GFE of the optimized structures by the M06-2X, absolute single-point energies and GFE of the optimized structures by other DFT methods, Cartesian coordinates of all of the stationary points (PDF)

in Table 7, the order of the relative Gibbs free energy barrier (i.e., ΔG‡(TS6RNHC1) = 12.8 kcal/mol < ΔG‡(TS6RNHC) = 14.4 kcal/mol < ΔG‡(TS6RNHC2) = 17.6 kcal/mol) is in agreement with the inverse order of their N values of M5NHCs (i.e., N(M5NHC1) = 4.210 eV > N(M5NHC) = 4.193 eV > N(M5NHC2) = 4.009 eV). Obviously, the efficiencies (i.e., the reaction rates) can be explained by the global nucleophilicity (N) values associated with the different NHC catalysts. Notably, the computed data reveal that the energy barrier via TS6RNHC2 (ΔG‡ = 17.6 kcal/mol) of the reaction model with 87% yield is higher than that via TS6RNHC (ΔG‡ = 14.4 kcal/ mol) involved in another reaction model with 71% yield, indicating the reaction efficiencies (i.e., the reaction rates) associated with the different NHCs have no direct correlation to the reaction yields in this kind of reaction.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yang Wang: 0000-0003-0695-385X Donghui Wei: 0000-0003-2820-282X

4. CONCLUSION In this paper, the comprehensive DFT calculations on the NHC-catalyzed oxidative [4 + 2] annulation of enal and alkenylisoxazole were performed to pursue a deep understanding of the detailed mechanisms and stereoselectivity. The most favorable pathway proceeds via the following steps: the nucleophilic addition of NHC to enal, [1,2]-proton transfer affording Breslow intermediate, oxidation of the Breslow intermediate by DQ, HCO3−-assisted γ-C(sp3)−H deprotonation with the presence of the reduced oxidant [DQH]−, rotation process, Michael addition, six-membered ring-closure process, and regeneration of catalyst NHC. The computed results demonstrate that the additive DQ mainly works as oxidant to accept two electrons and a proton via an HTO pathway during the oxidation process and plays a significant role in the γ-C(sp3)−H deprotonation process. The energy profiles reveal that the Michael addition is the rate- and stereoselectivity-determining step, and the energetically favor-

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial support from the National Natural Science Foundation of China (Nos. 21773214 and 21303167), the China Postdoctoral Science Foundation (Nos. 2015T80776 and 2013M530340), and the Outstanding Young Talent Research Fund of Zhengzhou University (No. 1521316001), and we thank the ACS ChemWorx Authoring Services for providing linguistic assistance.

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Insights into the N-Heterocyclic Carbene (NHC)-Catalyzed Oxidative Î³

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